Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress Olivier Berton, 1 Colleen A. McClung, 1 Ralph J. DiLeone,* Vaishnav Krishnan, 1 William Renthal, 1 Scott J. Russo, 1 Danielle Graham, 1 Nadia M. Tsankova, 1 Carlos A. Bolanos,† Maribel Rios, 2 Lisa M. Monteggia, 1 David W. Self, 1 Eric J. Nestler‡ Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences. T he mesolimbic dopamine pathway, composed of dopaminergic neurons in the midbrain ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc), allows an organism to iden-tify emotionally salient stimuli in the environ-ment, to learn about outcomes associated with those stimuli, and to express appropriate ap-proach or avoidance responses ( 1 , 2 ). Activation of this neural circuit has been characterized extensively in relation to drugs of abuse but has been less characterized in ethologically relevant contexts ( 3–5 ). The circuit is stimulated in humans and animals by psychosocial experi-ences such as affiliation and cooperation ( 6 , 7 ), and it drives associative learning processes such as imprinting, pair bonding, and maternal at-tachment ( 8 , 9 ). Aversive stimuli such as ag-gression and social subordination ( 10 ) also acutely activate the mesolimbic dopamine path-way ( 11–13 ) and have been linked to chronic alterations in dopaminergic function ( 14 ). These observations have led to the hypothesis that dopaminergic signaling to the NAc may be involved in the perception of social status and the appraisal of threats from the social environ-ment ( 8 ). Imaging studies have linked the NAc to cognitive processes that lead to the attribu-tion of salience to social stimuli ( 15 ). Alteration of this cognitive function could contribute to a social withdrawal trait that is common to sev-eral human affective disorders, including de-pression, social phobia, and post–traumatic stress disorder (PTSD), in which dopaminergic ab-normalities have been described ( 16–19 ). How-ever, very little is known about the mechanisms through which the motivational value of so-cially relevant stimuli might be encoded by this pathway. To characterize the neurobiological mecha-

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